Strategizing The Scale-Up Of Cell Therapy Manufacturing Capacity
A conversation with Mike Blankenstein, vice president – patient supply operations, Adaptimmune
Adaptimmune is one of the only cell therapy companies that has built an entire in-house manufacturing facility. Mike Blankenstein, vice president of patient supply operations at Adaptimmune, has been with Adaptimmune for nearly five years, bringing 25 years of manufacturing and supply chain experience in a variety of industries. He provides strategic direction, leadership, and oversight of clinical and commercial supply planning and materials management for Adaptimmune’s global manufacturing and patient supply. For the last 17 years he has worked in the pharmaceutical industry with Wyeth, Pfizer, and Johnson & Johnson. Mike holds a B.Sc. in mechanical engineering from Drexel University, an M.Sc. in engineering from University of Pennsylvania, and a Six Sigma Green Belt Certification from Villanova University. Below, he discusses Adaptimmune’s strategy for its cell therapy manufacturing facility and scaling up capacity.
Why did Adaptimmune decide to build an in-house manufacturing facility and why is it so important for your therapeutic area? Can you guide us through your decision-making process?
BLANKENSTEIN: Manufacturing and supply are more critical in cell therapy than other therapeutic areas. Innovation cycles are much faster because there are many ways to improve a cell therapy product by adapting the manufacturing process. At Adaptimmune, we believe that being an integrated company is key to success in cell therapy, as it allows us to translate our learnings into product innovation rapidly and efficiently.
We’ve adopted a centralized approach such that complexity can be managed within one facility. We believe that internal manufacturing enables greater flexibility and simplified decision-making. Each patient treated with our autologous T-cell receptor T-cell therapies is receiving their own engineered cells back. The attention and collaboration required for this process led us to build an integrated company, including a largely internal set of chemistry, manufacturing, and controls (CMC) and supply capabilities closely connected to the clinical, medical, and commercial teams. We continuously leverage learnings from our trials, research work, and translational science, as well as from peers and external partners, to rapidly iterate improvements into our integrated processes to maximize opportunities and mitigate risks.
The clinical strategy itself is an important consideration. As early clinical data can come from small patient populations, manufacturing complexity can be minimized through early-phase trial design that focuses on geography and/or a few clinical sites. This enables a broader range of clinical trials, reducing overheads from capacity, materials, and personnel. Implementing manufacturing improvements is considerably nimbler, as there are fewer associated regulatory changes accompanied by reduced internal change control burden.
The key decision driver centers on delivering high levels of efficiency and reliability for every patient. Best-in-class “vein to vein” operations and patient experience are critical to success. Manufacturing capacity and operations are based on the following targets:
Efficiency: Less than seven days for apheresed cells to enter the manufacturing process.
Reliability: RFT (right first time) manufacturing exceeds 95%, supporting a high likelihood of success while accepting minimal supply risk.
To meet these goals, we must not only successfully execute cell therapy product manufacturing but also enable scaling to supply additional patients in more geographies.
Internal vector and T-cell manufacturing are considered key strategic organizational capabilities, especially during clinical phase of product development. Gaining this self-sufficiency allows full control over cell therapy product manufacturing and process improvement and enables faster adoption of new technology to improve manufacturing and processing times. As more and more innovative and disruptive technical advances are developed, we must be able to evaluate and implement quickly. This internal capability allows us to scale appropriately, with selected partners, to meet commercial demand.
Adaptimmune required reduced reliance on external scheduling considerations that could hinder our ability to quickly react to the dynamic demand and supply landscape. Additionally, we required flexibility to quickly respond to positive clinical data that may result in increased demand and/or lead to additional trials. Therefore, we maintained capacity with an external manufacturing partner as a contingency while establishing our facility in the Philadelphia Navy Yard in a phased approach. A similar strategy has been applied to vector manufacturing.
In these early stages of development, we chose not to work with a CDMO for two reasons. First, flexibility of scheduling is a must for early-phase development. Patients presently treated with our therapies are heavily pretreated. They need rapid access to treatment alternatives. Accommodating patient treatment schedules is of utmost importance. Second, time-sensitive introduction of process improvements is imperative to cell and gene therapy success. In my opinion, the ability to assess and adopt new technologies is better enabled by in-house capabilities.
How have you planned for manufacturing space?
BLANKENSTEIN: Adaptimmune’s manufacturing network strategy is designed to evolve with us as the company grows, balancing cost and risk, while ensuring flexibility to respond to patients’ needs. We believe a low-cost, risk-aware supply volume approach followed by opportunistic capacity expansion provides flexibility in the short term. We have built integrated manufacturing, quality, process development, and supply capabilities to deliver TCR T-cell therapies to people with cancer.
A detailed analysis of current and projected demand has allowed us to optimize required manufacturing capacity, while maintaining service levels. Capacity planning starts with clinical dosing targets and experience-based assumptions to ensure we have manufacturing slots and materials needed to minimize patient wait time. To meet these targets, analyses of our capacity models suggests that some excess capacity must be maintained. The lower capacity utilization supports quicker response times.
Our autologous Center of Excellence in the Philadelphia Navy Yard was initially constructed to support clinical trial supply for North America and Europe of up to 25 patient batches per month, while allowing for expansion within the existing building’s footprint. The existing space comprises one culture room, two processing suites, and laboratories. Staffing initially supported eight to 10 slots per month, and we have subsequently increased headcount to achieve 15 to 20 slots per month in line with forecast increases.
What is your plan/strategy to meet future commercial manufacturing requirements?
BLANKENSTEIN: As we progress toward commercial manufacturing for our first-generation product, afamitresgene autoleucel (“afami-cel”), we have initiated expanding the facility to create two culture rooms and four processing suites. Our strategy calls for dedicating the existing space exclusively for the commercial manufacture of afami-cel and building out the additional space for cost-effective clinical manufacturing. This timing has been derived from clinical trial outcomes and facilitates global pivotal and commercial launch supply from the same manufacturing process and facility. Pending additional labor resources, the maximum capacity of the Navy Yard facility is up to 1,000 patient manufacturing runs per year.
Our strategic vision, pending additional clinical signals in larger indications, includes a new commercial facility capable of manufacturing for thousands of patients per year and, depending on where that additional capacity is placed, could also result in regional manufacturing strategies. Larger patient volumes would translate into greater capacity utilization and, ultimately, reduced costs. CDMO considerations at this later stage, when the process is essentially locked and in combination with internal capabilities, could provide greater agility as well as supply continuity.